Adenosine agonists such as N6-cyclohexyl and N6- phenylisopropyladenosine have been shown to exert profound effects on both cardiovascular and neurological function by virtue of their interaction with specific purinergic receptors. While structure-activity relationships for the A1 subtype of purinergic receptor have been defined, indicating preferential binding to N6-alkyl and aralkyl derivatives of adenosine, little information is known concerning the structural requirements for binding to A2 purinergic receptors. At present, only a few A2 selective agonists have been reported including 5'-(N- ethylcarboxamide) adenosine (NECA), 2-phenylaminoadenosine, and aristeromycin, although an extensive structure-activity study is lacking. In this proposal, a series of 5'-carboxamide analogs of N6-methyladenosine will be prepared, modeled after the known A2 receptor agonist NECA, in which the 5' substituent will be extended to include reverse carboxamides, heterocyclic, aromatic, tertiary, and amino acid-based carboxamides, imides, and esters, in order to determine what substituents at this key position promote A2 receptor binding. Biological evaluation will include both A1 and A2 receptor binding determinations, IC50 and Ki value determinations. Such structure-activity studies will hopefully provide a more complete picture of the A2 purinergic receptor, and thus facilitate the design of selective receptor agonists/antagonists. In addition, by employing such selective agents, a clearer picture of the cardiovascular/neurological consequences of A2 receptor occupation can be realized.